Patients with select premalignant oral lesions have a high risk of secondary lesions and oral squamous cell carcinoma (OSCC). Immune therapies hold promise for OSCC, but are discouraged by the immune suppression they induce. An alternative is immune treatment of patients with high risk premalignant lesions. We hypothesize that oral premalignant lesions can be used in dendritic cell vaccines to stimulate protective immunity targeting shared tumor antigens on premalignant lesions and OSCC. The rationale for this hypothesis is based on our studies showing that dysplastic premalignant lesions share overexpression of tumor antigens with OSCC. The most prominent shared antigens are epidermal growth factor receptor (EGFR), the receptor for advanced glycation end products (RAGE) and the MUC1 mucin. The specific aims that will test our hypothesis are: 1. To stimulate patient T-cell reactivity in vitro to premalignant lesions and OSCC using dendritic cells pulsed with autologous premalignant lesion cells and to determine if reactivity targets EGFR, RAGE and/or MUC1. a. To use premalignant lesion-pulsed dendritic cells in vitro to stimulate autologous T-cell reactivity to premalignant lesions and OSCC. b. To determine the extent to which the immune reactivity that is generated in response to premalignant lesion-pulsed dendritic cells is targeted at EGFR, RAGE and MUC1. 2. To skew the immune phenotype within premalignant oral lesions into protective immune reactivity against premalignant oral lesions and OSCC in a carcinogen-induced premalignant lesion mouse model. a. To determine if vaccination using dendritic cells pulsed with lysates of 4NQO-induced premalignant lesion cells skews the local immune phenotype into reactivity against premalignant lesions and OSCC. b. To determine in vivo if vaccination with dendritic cells pulsed with lysates of 4NQO-induced premalignant lesion cells stimulates protective immunity against premalignant oral lesions and OSCC. c. To determine the extent to which the protective immune reactivity that is generated in response to vaccination with premalignant lesion-pulsed dendritic cells is targeted at EGFR, RAGE and MUC1. d. To determine if vaccination with dendritic cells pulsed with peptides derived from EGFR, RAGE and MUC1 will confer protective immune reactivity to premalignant lesions and their progression to OSCC. These studies are expected to show that vaccination against premalignant oral lesions stimulates immunity against premalignant lesions and OSCC. Identifying the target antigens against which protective immunity is elicited allow use of peptides from these antigens in vaccines for patients at high risk for lesions and OSCC. PUBLIC HEALTH RELEVANCE: Oral squamous cell carcinoma is the 6th most common neoplasm in the world with a 5 year survival of less than 50%. The proposed studies have direct relevance to the goal of reducing oral cancer development from premalignant oral lesions.